3-38585800-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000335.5(SCN5A):​c.2678G>A​(p.Arg893His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R893C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

19
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:2O:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a intramembrane_region Pore-forming (size 20) in uniprot entity SCN5A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38585801-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 3-38585800-C-T is Pathogenic according to our data. Variant chr3-38585800-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38585800-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.2678G>A p.Arg893His missense_variant Exon 16 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.2678G>A p.Arg893His missense_variant Exon 16 of 28 ENST00000423572.7 NP_000326.2 Q14524-2Q86V90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkc.2678G>A p.Arg893His missense_variant Exon 16 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.2678G>A p.Arg893His missense_variant Exon 16 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250868
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135804
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461782
Hom.:
0
Cov.:
36
AF XY:
0.00000138
AC XY:
1
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brugada syndrome Pathogenic:3Other:1
Nov 10, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 893 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region (a.a.718-938) at transmembrane domain DII. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes a loss-of-function phenotype with no detectable channel current in transfected HEK293 cells (PMID: 25904541). This variant has been reported in over ten unrelated individuals affected with Brugada syndrome (PMID: 19356768, 20381179, 23503384, 25904541 , 28341781, 29759671, 32298319, 32893267, 35052356, 36091819, 37061847, 37547970, ClinVar SCV000832454.4, doi:10.3329/cardio.v15i1.61916), in two individuals suspected of having Brugada syndrome (PMID: 20381179, ClinVar SCV000617274.1), and in another individual affected with sudden unexplained death (PMID: 29247119). This variant has been reported to be a de novo occurrence in one of the affected carriers without confirmation of paternity and maternity (PMID: 35052356). This variant has been identified in 1/250868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jul 19, 2023
Genetics and Molecular Pathology, SA Pathology
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SCN5A c.2678G>A variant is classified as Likely Pathogenic (PS3_Moderate, PS4_Moderate, PM1, PM2, PP3) The SCN5A c.2678G>A variant is a single nucleotide change in exon 16/28 of the SCN5A gene, which is predicted to change the amino acid arginine at position 893 in the protein, to histidine. The variant has been reported in greater than 6 probands with a clinical presentation of Brugada syndrome/SCD (PMID#25904541, 20129283, 29247119, 29759671, ClinVar)(PS4_Moderate) and is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom) (PM2). Functional studies in HEK-293 cells show a deleterious effect of this variant with no current reported in a patch clamp assay, however, additional functional evidence is required to confirm the impact of this variant (PMID#25904541)(PS3_moderate). This variant is located in the functionally important DII S5/S6 transmembrane spanning region of the SCN5A protein (PM1) and computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs199473172), is reported as disease causing in the HGMD database (CM100679) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar #67749). -

-
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

May 24, 2024
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Heterozugous varint NM_198056.3:c.2678G>A (p.Arg893His) in the SNC5A gene was found in male proband (27 y.o., Caucasian) with spontaneous Brugada pattern, syncope, VT, ICD implanted (PMID: 36091819). Family history burdened with SCD before 40 years of age. This variant is in The Genome Aggregation Database (gnomAD) v4.1.0 with total MAF 0.000002478 (Date of access 23-05-2024). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and Enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Likely Pathogenic with following criteria selected: PM1_Strong, PM2, PP3. -

not provided Pathogenic:1Uncertain:1
Sep 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 893 of the SCN5A protein (p.Arg893His). This variant is present in population databases (rs199473172, gnomAD 0.004%). This missense change has been observed in individuals with Brugada syndrome (PMID: 20129283, 20381179, 23503384, 28341781, 29247119; internal data). ClinVar contains an entry for this variant (Variation ID: 67749). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 25904541). This variant disrupts the p.Arg893 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28341781; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 24, 2021
GeneDx
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

Identified in several patients referred for Brugada syndrome genetic testing (Kapplinger et al., 2010), in patients with sudden unexplained death and suspected Brugada syndrome (Lin et al., 2017; Tadros et al., 2017), and in one individual with reported Brugada pattern on EKG referred for genetic testing at GeneDx; however, details confirming a clinical diagnosis of Brugada syndrome were not provided; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro cellular electrophysiology studies suggest this variant results in no detectable channel current in transfected HEK-293 cells; however, details of the functional analysis were not provided (Kapplinger et al., 2015); A missense variant in the same residue (R893C) has been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#67749; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23503384, 28341781, 24136861, 20129283, 25904541, 29247119, 30662450, 29759671, 30193851) -

Cardiovascular phenotype Pathogenic:1
Sep 25, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R893H variant (also known as c.2678G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2678. The arginine at codon 893 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in multiple individuals with features consistent with Brugada syndrome and in Brugada syndrome cohorts, but clinical details were limited in some cases (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Chinushi M et al. Pacing Clin Electrophysiol, 2011 Jan;34:e1-5; Doetzer AD et al. Int. J. Cardiol., 2011 Aug;150:e96-7; Tadros R et al. JACC Clin Electrophysiol, 2017 12;3:1400-1408; Yamagata K et al. Circulation, 2017 Jun;135:2255-2270; Wijeyeratne YD et al. Circ Genom Precis Med. 2020 Dec;13(6):e002911; Zaklyazminskaya E et al. Front Pharmacol. 2022 Aug;13:984299; Pannone L et al. Europace. 2023 May;25(5); Pham HM et al. Mol Genet Genomic Med. 2023 Dec;11(12):e2263). In an assay testing SCN5A function, this variant showed a functionally abnormal result (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1
Jun 28, 2016
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.5
.;H;.;.;.;H;.;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-4.8
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;.;D;D;.;.
Vest4
0.98
MutPred
0.90
Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP
0.99
MPC
1.3
ClinPred
1.0
D
GERP RS
4.2
Varity_R
0.96
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473172; hg19: chr3-38627291; API